Date Published: April 4, 2013
Publisher: Public Library of Science
Author(s): Sylvie François, Sarah Vidick, Mickaël Sarlet, Daniel Desmecht, Pierre Drion, Philip G. Stevenson, Alain Vanderplasschen, Laurent Gillet, Samuel H. Speck.
Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi’s Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68), are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naïve males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent the spread of these viruses in natural populations.
Herpesviruses are important pathogens which are ubiquitous in both human and animal populations. They establish persistent, productive infections, with virus carriers both making anti-viral immune responses that protect against disease and excreting infectious virions. Among herpesviruses, gammaherpesviruses establish a long-term latent infection of circulating lymphocytes. They drive lymphocyte proliferation as part of normal host colonization and consequently they can induce some lymphoproliferative disorders. In humans, Epstein-Barr virus (EBV) and the Kaposi’s Sarcoma-associated Herpesvirus (KSHV) are associated with several human malignancies such as Burkitt’s and Hodgkin’s lymphomas, nasopharyngeal carcinoma, Kaposi’s sarcoma and post-transplant lymphoproliferative disease , . Human cancers associated with these two viruses are particularly prevalent in Africa where they are linked to malaria  and human immunodeficiency virus-1 (HIV-1) infection . More generally, individuals with inherited or acquired immunodeficiency have an increased risk of developing a malignancy caused by one of these two viruses . Efficient control of these infections is therefore of major interest, particularly in some epidemiological circumstances.
Transmission in host population is the main motor of viral evolution –. Herpesviruses have co-evolved with their host for millions of years and have therefore developed sophisticated mechanisms to persist and transmit in presence of protective immune response , . This is particularly the case for gammaherpesviruses , , . Until now, most of the immune evasion strategies of gammaherpesviruses have been studied in vitro or in animal models , , . However, none has been investigated in the light of transmission mainly due to the lack of experimental transmission model. In this study, using in vivo imaging, we observed that MHV-68 is genitally excreted after latency establishment in intranasally infected female mice (Figures 1–3, S1 and S2). This allowed us to observe, for the first time, experimental transmission to naïve males after sexual contact (Figures 6–9).